Nipah virus (NiV) is a zoonotic paramyxovirus that caused an explosive disease outbreak in Malaysia in 1998 involving humans and pigs. It was brought under control only after culling of ~one million pigs. The ongoing activity of the virus in Bangladesh, it's highly lethal nature and person-to-person spread in some cases, and the potential of the virus as an agent of agroterror are all concerns compounded by the fact that at present there is no effective way to prevent or treat NiV disease. The potential of the virus to cause disease in humans and animals in other geographic regions because of wide distribution of NiV-carrying fruit bats across the world and easier person-to-person transmission because of high mutation rates associated with RNA viruses adds to these concerns. Two NiV vaccination strategies, namely a soluble G protein subunit approach, and poxvirus vector-based method have been evaluated experimentally. They both have concerns as human use vaccines in terms either of safety or effectiveness. We are exploring NiV virus-like particles (VLPs) as vaccine. VLPs are highly effective and safe immunogens because they are made only from selected viral proteins which spontaneously assemble into virus-like structures morphologically and immunologically. We have recently reported the first evidence for the potential of a paramyxovirus VLP vaccine composed native proteins: NiV VLPs composed of G, F and M proteins had many virus-like properties in vitro including their fusogenic property, and their ability to induce neutralizing antibody response in vivo. Here we propose to evaluate protective efficacy of these particles in an animal model of NiV disease. Since fusogenicity may have implications for vaccine potency, we will test non-fusogenic VLPs in parallel for comparative purposes. We have shown the feasibility of undertaking all the proposed studies because we have established a scale-up method to generate VLP quantities required for the proposed work. Our hypothesis is that NiV VLP vaccine will be safe, and will generate protective immune responses. The specific aims of the project are to 1) Evaluate immunogenicity and safety of NiV VLPs. Animals will be vaccinated intramuscularly. Optimal concentration of NiV VLPs formulated with and without adjuvant, and the vaccination schedule that induces the best neutralizing antibody response will be determined. Non-fusogenic particles and y-irradiated NiV will be tested in parallel for comparative purposes. The effectiveness of the VLPs to induce T-cell memory recall response will also be tested. 2) Evaluate protective efficacy of NiV VLPs. LD50 dose of the challenge NiV virus by intranasal route will be determined. Controls and the vaccinated group(s) with optimal immunity will be challenged intranasally with 10LD50 virus dose. Animal protection rate and the post-challenge evaluation will determine the type of protection afforded by the vaccine. We expect that NiV VLPs will be highly effective as vaccine. Importantly, the information gleaned from our studies will direct the development of much needed vaccines for other paramyxoviruses. PUBLIC HEALTH RELEVANCE: Our work in the laboratory and in mice has shown for the first time, the potential of virus-like particles (VLPs) as vaccine to prevent Nipah virus (NiV) disease. Next, this vaccine needs to be tested in an animal model of NiV disease as proposed here. The significance of this innovative research is that the knowledge gained from these studies will open up possibilities for developing VLP vaccines for other paramyxoviruses including those of public health concern worldwide, such as respiratory syncytial virus, for which vaccines have remained elusive for decades.